Dataset Information

Molecular Glue Degraders of the RNA Binding Protein HuR to Treat BRAF-Mutant Colorectal Cancer

ABSTRACT: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all colorectal cancer (CRC) patients, and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as Encorafenib are ineffective due to MAP kinase pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, though approved therapies, results in short survival benefits and frequent treatment resistance and relapse1-3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumor growth, invasion, and therapy resistance. dHuR binds the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by Cryo-EM structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF mutant CRC tumors including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat refractory BRAF-mutant CRC patients.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yong Cang

PROVIDER: PXD072281 | iProX | Sun Dec 21 00:00:00 GMT 2025

REPOSITORIES: iProX

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Publications

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.

Lu Xiaocui X Wang Xiuyun X Yang Zheng Z Wang Xusheng X Wang Lin L Xu Chunhui C Lo I-Chung IC Geng Chenlu C Wang Lin L Pu Yisheng Y Zhang Keyu K Zhu Ziqiang Z Ye Lanxin L Huang Jiayuan J Wei Xiaofan X Bai Fang F Zhu Yanan Y Qian Xiaobing X Dou Hao H Su Hexiu H Cang Yong Y

Nature 20260610

BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse<sup>1-3</sup>. Here, through rational chemical ...[more]

PMID: 42271059

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Project description:The colorectal epithelium is a rapidly renewing tissue, with a remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. Activation of oncogenic MAPK signalling in CRC is common, with mutations frequently found in both KRAS (40-50%) and BRAF (10%), alongside other mechanisms of EGFR pathway upregulation. Nonetheless, inhibition of this pathway is often linked to rapid therapeutic resistance in patients. Given the recent development of KRAS inhibitors and the licensing of BRAF+EGFR inhibitor combinations we have investigated mechanisms of resistance to these agents in complex mouse models of CRC. Here we show that MAPK signalling supports the regenerative/revival stem cell phenotype in vivo, while its inhibition leads to rapid remodelling of both Kras and Braf mutant mouse models to a high Wnt activity canonical stem cell phenotype marked by expression of Lgr5. This results in acute therapeutic resistance in Kras driven, and delayed resistance in Braf driven models. Importantly, where therapeutic MAPK targeting is applied in the presence of a single regenerative epithelial population, such as early metastatic disease, or where plasticity is restrained, for example through Wnt pathway restriction, a marked impact on tumourigenesis is observed. Modelling of an BRAF and RNF43-mutant patient population, clinically super-responders to BRAF/EGFR inhibitor therapy, demonstrates excellent response to therapy due to restricted epithelial plasticity, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provide clear insight into the mechanisms underpinning resistance to targeting oncogenic MAPK signalling in CRC. Moreover, we demonstrate that strategies that aim to restrict epithelial plasticity or corral into or intervene when tumours are in a regenerative cell fate may improve efficacy of MAPK targeting agents in CRC.

Dataset Information

Molecular Glue Degraders of the RNA Binding Protein HuR to Treat BRAF-Mutant Colorectal Cancer

Publications

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.

Similar Datasets

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